Urinary tract infection (UTI) is one of the most commonly acquired bacterial infections leading to a physician consultation. UTIs are estimated to account for 7 million office visits per year and 1 million visits to the emergency department, leading to an economic impact of $1.6 billion annually (Foxman (2002) Am J Med. 113(Suppl 1A):5S-13S; herein incorporated by reference in its entirety). Uropathogenic Escherichia coli (UPEC) are the leading cause of UTI and account for up to 90% of uncomplicated infections (Foxman and Brown (2003) Infect. Dis. Clin. North Am. 17:227-41; herein incorporated by reference in its entirety). Antimicrobial therapy, the leading treatment for UTI, has become increasingly complicated by the rise of antimicrobial resistance among urinary tract pathogens. Furthermore, persistent and recurrent UTIs present a clinical challenge, given the absence of a widely protective and effective preventative therapy for UTI.
Vaccine design and development for the prevention and/or treatment of UPEC infection has been impeded by a limited understanding of the host immune responses during UTI. Characterizations of innate and adaptive immune responses to UPEC during UTI indicate that infection produces abundant pathogen-associated inflammatory responses. Several UPEC-targeted vaccine candidate strategies have been evaluated, including vaccines against pilus adhesins FimCH, PapDG and Dr adhesion and vaccines directed against non-adhesin UPEC virulence factors such as hemolysin and IroN (Foxman and Brown (2003) Infect. Dis. Clin. North Am. 17:227-41; Langermann et al. (2000) J Infect. Dis. 181:774-8; Langermann et al. (1997) Science 276:607-11; Palaszynski et al. (1998) Dev. Biol. Stand. 92:117-22; Roberts et al. (2004) J Urol. 171:1682-5; Hull et al. (2002) Infect. Immun. 70:6481-4; Goluszko et al. (2005) 73:627-31; Russo et al. (2003) Infect. Immun. 71:7164-9; O'Hanley et al. (1991) Infect. Immun. 59:1153-61; each herein incorporated by reference in their entireties). Additionally, limited success has been achieved through vaccination against UTI by using vaginal, nasal or oral administration of killed preparations of UPEC (Hopkins et al. (2007) J Urol. 177:1349-53; Layton and Smithyman (1983) Clin. Exp. Immunol. 54:305-12); Grischke and Ruttgers (1987) Urol. Int. 42:338-41; Uehling et al. (1994) 151:214-6; Uehling et al. (1991) J Urol. 146:223-6; Uehling et al. (1990) J Urol. 143:143-5; Uehling et al. (1987) J Urol. 137:327-9; Russo et al. (2007) Vaccine 25:3859-70; each herein incorporated by reference in their entireties). A more systematic approach has been recently applied to identify potential vaccine antigens expressed in the outer membrane which provide protection against challenge after vaccination (Hagan and Mobley (2007) Infect. Immun. 75:2679-88; Alteri and Mobly (2007) Infect. Immun. 75:3941-9; each herein incorporated by reference in their entireties). Despite these efforts, no reliable vaccine strategy has been widely employed for UTI, indicating the need for alternative UTI vaccine strategies.
UPEC present further challenges to treatment and prevention. Intracellular invasion of and biofilm formation in host urothelial cells by UPEC strains has been demonstrated in both animal models and in human UTI patients (Garafalo et al. (2007) Infect. Immun. 75:52-60; Rosen et al. (2007) PLoS Med. 4:e329; Justice et al. (2006) PNAS 103:19884-9; Anderson et al. (2003) Science 301:105-7; each herein incorporated by reference in their entireties). These biofilm-type UPEC are more resistant to host clearance and may be more resistant to antimicrobial therapy (Justice et al. (2006) PNAS 103:19884-9; Mulvey et al. (2001) Infect. Immun. 69:4572-9; Schilling et al. (2002) Infect. Immun. 70:7042-9; each herein incorporated by reference in their entireties). Some have hypothesized that chronic colonization and recurrent UTI by UPEC could be due, in part, to the intracellular invasion and biofilm formation. Another possible explanation for recurrent UPEC infection is that deficiencies in host innate and/or adaptive immune responses prevent the development of lasting protective immunity to re-infection. Given these challenges, new strategies are warranted for the development of multifunctional approaches to UPEC vaccine design which bolster the immune response and eradicate intracellular bacterial reservoirs.
Accordingly, there is need in the art for improved methods and vaccines to prevent and treat bacterial infection, particularly urinary tract infection.